Project Summary The stereoselective construction of saturated heterocycles and carbocycles remains an important challenge in organic synthesis, as many pharmaceutically relevant molecules and biologically active natural products contain these subunits. Although the development of methods for the construction of heterocycles and carbocycles has been of longstanding interest, a number of important targets are difficult to generate in a stereoselective manner using existing transformations. In addition, many methods are not readily amenable to the preparation of numerous analogs from a single precursor. The long-term goal of our research program is to develop new reactions for the construction of enantiomerically enriched, biologically active molecules. The objectives of the research outlined in this proposal, are to develop new alkene difunctionalization reactions for the construction of useful heterocycles and carbocycles, to develop new catalysts for alkene difunctionalization reactions, and to gain insight into factors that facilitate alkene heteropalladation and sp3C?N bond-forming reductive elimination. These objectives will be achieved by pursuing two specific aims: (1) to prepare functionalized carbocycles via alkene difunctionalization reactions between alkenes bearing pendant carbon-centered electrophiles and exogenous nucleophiles; and (2) to prepare substituted heterocycles via alkene difunctionalization reactions that employ nitrogen-centered electrophiles. The proposed studies are innovative because they will explore fundamentally new reactivity, such as the use of allylic electrophiles, nitrogen-centered electrophiles, or chiral enamine nucleophiles in Pd-catalyzed alkene difunctionalization reactions. Our experiments will result in new catalysts that facilitate challenging anti-heteropalladation reactions of hindered alkenes, which have been implicated as key steps in other synthetically useful transformations. These studies will also provide insight into factors that facilitate sp3C?N bond-forming reductive elimination from Pd(II), which is a rare step in catalysis, but has the potential to be broadly used as a key step in new reactions that lead to C?N bond formation. This knowledge will be of significant utility in the future development of other new palladium-catalyzed transformations. The proposed research is significant because the new transformations developed during these studies will provide access to important biologically active compounds that are difficult to generate with existing methods. This will broaden the range of carbocyclic and heterocyclic building blocks available for use in medicinal chemistry/drug development. In addition, these new transformations will also allow for facile generation of analogs of interesting molecules, that differ in either their stereochemistry or in the nature of their substituents, which can be used to optimize biological or pharmaceutical properties of lead compounds.